Cigarette smoking during pregnancy and risk of preeclampsia: A systematic review

AJOG REVIEWS

Cigarette smoking during pregnancy and risk of preeclampsia: A systematic review Agustin Conde-Agudelo, MD, Fernando Althabe, MD, José M. Belizán, MD, PhD, and Ana C. Kafury-Goeta, MD Montevideo, Uruguay In this systematic review of the existing evidence regarding the relationship between cigarette smoking during pregnancy and preeclampsia, studies were found through searches of MEDLINE (1966–October 31, 1998), Embase, Popline, CINAHL, Lilacs, bibliographies of identified studies, and proceedings of meetings on preeclampsia, and also through contact with relevant researchers. No language restrictions were imposed. Only cohort and case-control studies dealing with the relationship between cigarette smoking and preeclampsia were considered. Assessment of methodologic quality and data extraction of each study were carried out by 2 authors working independently. Typical relative risks and odds ratios with 95% confidence intervals were calculated for cohort and case-control studies, respectively, with both fixed and random effects models. Twenty-eight cohort studies and 7 case-control studies including a total of 833,714 women were included. All cohort studies reported an inverse association between cigarette smoking during pregnancy and incidence of preeclampsia (typical relative risk, 0.68; 95% confidence interval, 0.67-0.69). The findings were similar for case-control studies (typical odds ratio, 0.68; 95% confidence interval, 0.57-0.81). An inverse dose-response relationship was also found. Pooled data from cohort and case-control studies showed a lower risk of preeclampsia associated with cigarette smoking during pregnancy. (Am J Obstet Gynecol 1999;181:1026-35.)

Key words: Cigarette smoking, meta-analysis, preeclampsia, review

Smoking during pregnancy has been associated with a variety of adverse pregnancy outcomes, such as increased risk of spontaneous abortion, low birth weight, prematurity, intrauterine growth restriction, abruptio placentae, placenta previa, and perinatal death.1-3 Paradoxically, the risk of preeclampsia has been consistently observed during the past 3 decades to be lower among smokers than among nonsmokers.4 Some authors5 have mentioned methodologic limitations of studies reporting the relationship between smoking in pregnancy and risk of preeclampsia, however, such as lack of distinction between hypertensive states associated with proteinuria and those without proteinuria, lack of an accurate and detailed history of cigarette smoking during conception and throughout each trimester of pregnancy, lack of information with respect to the effect of smoking cessation before and during pregnancy, the possible misleading

From the Latin American Center for Perinatology and Human Development, Pan American Health Organization, World Health Organization. Reprint requests: Agustin Conde-Agudelo, MD, Hospital de Clinicas, piso 16, Casilla de Correo 627, 11000 Montevideo, Uruguay. Copyright © 1999 by Mosby, Inc. 0002-9378/99 $8.00 + 0 6/1/100652

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measure of exposure by means of self-reports of number of cigarettes smoked per day, and the exclusive use of univariate analyses for statistical methods, ignoring the presence of potential confounding factors associated with both smoking and preeclampsia. In view of these methodologic problems we undertook further elucidation of this possible “protective” effect of cigarette smoking on preeclampsia through the use of meta-analytic techniques. The primary aim was to assess, from the best available evidence, the effects of cigarette smoking during pregnancy on the incidence of preeclampsia. If cigarette smoking were found to be related to preeclampsia, a secondary aim would be to evaluate the presence of a doseresponse gradient. Material and methods Data sources. Computerized searches were carried out in MEDLINE (1966 through October 31, 1998), Embase (1974 through October 31, 1998), Popline (1982 through October 31, 1998), CINAHL (1982 through October 31, 1988), and Lilacs (1982 through October 31, 1998) with the following MeSH and key word terms: smoking or tobacco and preeclampsia or eclampsia or gestosis,

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EPH or pregnancy toxemia or pregnancy-induced hypertension. Index Medicus (1955-1966), proceedings of several international meetings on preeclampsia, and references quoted in retrieved articles were also searched by hand. No language restrictions were imposed. Multiple articles resulting from the same data source were included only once in the systematic review. However, if 2 studies came from the same data source but spanned nonoverlapping periods of data accrual, they were both included in the systematic review. To find unpublished studies we contacted relevant researchers in the field. Study selection. The scope of the systematic review encompassed all cohort and case-control studies dealing with the relationship between cigarette smoking during pregnancy and preeclampsia as a primary or secondary outcome. Studies were included if they met the following minimal criteria: (1) The definition of cigarette smoking was clearly established; (2) the definition of preeclampsia corresponded to hypertension after 20 weeks’ gestation plus proteinuria; (3) the studies provided the necessary information to construct a 2 × 2 table and calculate the odds ratio or relative risk and their confidence intervals. Studies were excluded if they were case series or reports, editorials, or reviews; if risk estimates or confidence intervals were not published and sufficient information to calculate them could not be retrieved; or if they examined only the relationship between cigarette smoking and hypertensive states without proteinuria. All published studies deemed suitable were retrieved. The methods sections with study identifiers were removed and reviewed independently and in duplicate by 2 authors (A.C.-A. and A.C.K.-G.) to determine inclusion. Disagreements were resolved through consensus. The degree of agreement was expressed as percentage agreement and as κ.6 Methodologic quality. The methodologic quality of each included study was assessed in 3 areas deemed to be of importance for observational studies7-9: (1) adjustment of risk estimates for potentially confounding factors, (2) use of strategies to minimize bias, and (3) report of dose-response gradient. The articles were scored according to 7 items distributed among these criteria, providing a maximum total score of 9 points (see Appendix). Studies were allocated to 3 quality categories. High-quality studies were those that scored >6 points, medium-quality studies were those that scored 4 to 6 points, and low-quality studies were those that scored <4 points. Assessment of methodologic quality of each study was carried out by 2 of the authors (A.C.-A. and F.A.) working independently. Any differences of opinion that arose were resolved by discussion between these 2 authors. Data extraction. Data were extracted independently by 2 investigators (A.C.-A. and A.C.K.-G.). Discrepancies were resolved through consensus. Where outcomes were

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published in the form of percentages or graphs, the numbers of events were calculated. Information about maternal smoking was categorized into nonsmokers (women who had never smoked or were not smoking during pregnancy) and smokers (women who smoked daily during pregnancy). If the study provided sufficient data, smokers were subdivided into 2 categories according to the number of cigarettes smoked per day: moderate (1-9 cigarettes/d) and heavy (≥10 cigarettes/d). Data on the type of study design (ie, cohort or case-control studies) and the country where the study was carried out were also ascertained. Data analysis. Studies of different designs (ie, cohort and case-control studies) were analyzed separately because of differing threats to their internal validity.10 Data that were abstracted from each study were arranged in 2 × 2 tables, and 0.5 was added to cells that contained no observations to improve the precision of the effect measure.11 We calculated odds ratios for case-control studies and relative risks for cohort studies with their 95% confidence intervals as the effect measure on the basis of the data abstracted from each study. Then the typical relative risks and typical odds ratios were calculated with the Rothman and Boice12 and Mantel-Haenszel13 methods, respectively. The corresponding 95% confidence intervals were obtained according to the method of Greenland and Robins.14 We used the Q test15 to determine whether there was significant heterogeneity of effect across the studies. If there was no such evidence (P > .05), we calculated the typical relative risk and odds ratio with a fixed-effects model. In the presence of significant heterogeneity in the effect measure among studies being compared, we performed a random-effects analysis that was based on the method described by DerSimonian and Laird.16 To examine the validity of our systematic review we prepared a funnel plot to detect biases, mainly publication and location biases. We used the regression approach to assess funnel plot asymmetry as described by Egger et al.17 By means of simple nonweighted linear regression the standard normal deviate (defined as the odds ratio divided by its SE) was regressed against the estimate’s precision (defined as the inverse of the SE). The larger the deviation of the intercept of the regression line from 0, the greater was the asymmetry and the more likely it was that the meta-analysis would yield biased estimates of effect. As suggested by Egger et al,17 we considered P < .1 to indicate significant asymmetry. All statistical analyses were performed with Arcus Quickstat Statistical software (version 1.0; Addison Wesley Longman Limited, London, United Kingdom) and RevMan 3.0 (Cochrane Review Manager; Cochrane Collaboration, Oxford, United Kingdom). Subgroup and sensitivity analysis. To test the robustness of the overall findings, analyses were carried out for

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Table I. Characteristics of included studies reporting on relationship between cigarette smoking and preeclampsia Study

No. of patients

Year

Country

1959 1963 1965 1967 1967 1968 1969 1969 1971 1972 1973 1973 1976 1976 1982 1982 1986 1992 1995 1995 1997 1997 1997 1997 1998 1998 1998

United States United States United States Venezuela United States United Kingdom United Kingdom United Kingdom Sweden United Kingdom Sweden Australia United States United Kingdom United Kingdom United Kingdom United States United States United States United States Sweden United Kingdom United States Canada United States Sweden Holland

1989

Canada

677

Eskenazi et al45

1991

United States

261

Klonoff-Cohen et al46

1993

United States

225

Stone et al47

1994

Italy

585

Spinillo et al48

1994

United States

19,034

Ansari et al49

1995

United States

2,183

Lain et al50

1998

United States

100

Cohort studies Lowe18 Zabriskie19 Underwood et al20 Kizer21 Underwood et al22 Russell et al23 Duffus and MacGillivray24 Butler and Alberman25 Kullander and Källén26 Andrews and McGarry27 Palmgren et al28 Cope et al29 Hollingsworth et al30 De Souza et al31 Ounsted and Scott32 Cardozo et al33 Hoff et al34 Savitz and Zhang35 Sibai et al36 Coonrod et al37 Cnattingius et al38 Wong and Bauman39 Sibai et al40 Ananth et al41 Newman et al42 Ros et al43 Knuist et al44 Case-control studies Marcoux et al5

1,823 2,000 4,440 1,916 48,494 1,653 2,543 14,580 4,098 12,766 3,927 4,416 316 1,922 905 2,000 1,700 185,062 2,645 10,489 295,911 85,674 4,310 86,224 18,370 10,112 2,353

Participant

Quality score

All parities All parities All parities All parities All parities All parities Primigravid patients All parities All parities All parities All parities All parities Adolescent primiparous patients All parities All parities All parities All parities All parities Nulliparous patients All parities; single and twin pregnancies Nulliparous patients All parities Nulliparous patients All parities Primigravid patients Nulliparous patients aged <34 y Nulliparous patients

3 4 3 3 5 4 5 4 5 4 4 3 2 3 4 5 4 8 8 7 8 7 7 7 9 8 7

Case patients were primiparous women with diagnosis of preeclampsia and no history of high blood pressure before pregnancy; control patients were primiparous women with neither diagnosis of preeclampsia nor history of high blood pressure before pregnancy Case patients were women with discharge diagnosis of severe preeclampsia or eclampsia; control patients were women without discharge diagnosis of any hypertensive disorder of pregnancy Case patients were nulliparous with diagnosis of mild or severe preeclampsia or eclampsia and without concurrent diseases; control patients were nulliparous without diagnosis of preeclampsia, eclampsia, or concurrent diseases Case patients were women with diagnosis of preeclampsia and no history of diabetes, renal disease, or chronic hypertension; control patients were normotensive women with no history of renal disease, diabetes mellitus, or chronic hypertension Case patients were women with discharge diagnosis of severe preeclampsia; control patients were women without discharge diagnosis of hypertensive disorder Case patients were women with pregnancies complicated by eclampsia and no history of diabetes or chronic renal disease Case patients were nulliparous with preeclampsia; control patients were nulliparous without preeclampsia

8

7

7

6

8

7 8

All the studies included only women with single pregnancies except that of Coonrod et al,37 which included both singleton and twin pregnancies.

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Fig 1. Association between cigarette smoking during pregnancy and preeclampsia in cohort studies. CI, Confidence interval; RR, relative risk; singl, singletons.

several subgroups that met previously specified criteria. Subgroups for cohort studies included the following: (1) comparison of high-quality studies versus medium-quality studies and low-quality studies, (2) comparisons of studies of <200 women with preeclampsia versus ≥200 women with preeclampsia, (3) comparison of fixed-effects versus random-effects statistical model, (4) comparison of aim of hypothesis as primary versus secondary, and (5) comparison of geographic location of study in terms of Europe versus America versus Oceania. To test a dose-response gradient effect, additional meta-analyses were performed for both cohort and case-control studies in which women had been grouped as moderate and heavy smokers. Results Selected studies. A total of 42 publications were found, 8 of which were excluded. Thirty-three were found in the computerized search and 7 were found by reference checking. Two studies were located in abstract form, and their authors provided additional data. Thirty-four articles met our inclusion criteria.5, 18-50 The overall agreement on the inclusion of articles was 100%. One publication37 furnished information on 2 independent cohorts,

and this report was treated as 2 separate studies in the meta-analysis. Thus most of the analyses described here refer to 35 studies. Among the included studies (Table I) sample size ranged from 100 patients50 to 295,91l patients38 (833,714 patients overall). The studies included in this review varied in methodologic quality. Ten cohort studies35-44 and 6 case-control studies5, 45, 46, 48-50 were considered to be of high quality. The other 18 studies had ≥1 methodologic flaw. The most common shortcomings were in the areas of adjustments and bias. Interrater agreement on the scale was good (agreement, 88%; κ = 0.76.). Most disagreement was caused by slight differences in interpretation and was easily resolved. Finally, consensus was reached in all cases. Sixteen studies (47.1%) were conducted in the United States, 8 (23.5%) were conducted in the United Kingdom, 4 (11.8%) were conducted in Sweden, and the remaining came from Canada, Italy, Australia, Venezuela, and Holland. With respect to design, a total of 27 (79.4%) were cohort studies and the remainder were case-control studies. In 8 (23.5%) studies* analysis of the relationship between cigarette smoking and preeclampsia was stated to be a pri*References 5, 24, 28, 38, 42, 46, 48, and 50.

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Fig 2. Association between cigarette smoking during pregnancy and preeclampsia in case-control studies. OR, Odds ratio; CI, confidence interval.

Table II. Sensitivity analysis of meta-analysis of cohort studies assessing relationship between cigarette smoking during pregnancy and preeclampsia Subgroup

No. of studies

Typical relative risk

95% Confidence interval

27 27

0.68 0.70

0.67-0.69 0.67-0.73

10 17

0.67* 0.70*

0.66-0.70 0.67-0.72

10 17

0.65* 0.68*

0.57-0.75 0.67-0.70

4 23

0.65* 0.69*

0.62-0.69 0.67-0.70

13 13 1

0.68* 0.68* 0.69*

0.66-0.70 0.66-0.70 0.60-0.80

Statistical model Fixed effects Random effects Study quality High35-44 Low and medium18-34 Study size <200 women with preeclampsia† ≥200 women with preeclampsia‡ Aim of hypotheses Primary24, 28, 38, 42 Secondary§ Geographic location of study United Statesll Europe¶ Australia29 *Fixed effects. †References 18, 19, 21, 23, 24, 30, 32, 33, 36, and 44. ‡References 20, 22, 25-29, 31, 34, 35, and 37-43. §References 18-23, 25-27, 29-37, 39-41, 43, and 44. llReferences 18-22, 30, 34-37, and 40-42. ¶References 23-28, 31-33, 38, 39, 43, and 44.

mary aim. In the remaining studies information on this relationship was included but was accorded secondary status. Eight studies that reported findings regarding cigarette smoking and preeclampsia were not included in the meta-analysis. One study51 reported no significant association between cigarette smoking during pregnancy and preeclampsia, but no quantification of risk was given. Another study,52 a nested case-control study of risk factors for preeclampsia, found that smokers during pregnancy had a reduced risk of preeclampsia (adjusted odds ratio, 0.6; 95% confidence interval, 0.5-0.8), but sufficient information to construct a 2 × 2 table was not provided. Another article examined the effect of smoking on the risk of gestational hypertension but not preeclampsia.53 The remaining excluded studies54-59 were review articles.

Cohort studies. As shown in Fig 1, all cohort studies reported an inverse association between cigarette smoking during pregnancy and preeclampsia. In 19 of the 28 studies (68%) this reduction was statistically significant. The overall effect was a reduction in the risk of preeclampsia of 32% (95% confidence interval, 31%-33%). Although the test of heterogeneity found that the cohort studies were not statistically homogeneous (Q test for relative risks, 59.6; P = .0003), the sensitivity and subgroup analyses nonetheless showed that the overall estimates were very similar (Table II). Case-control studies. All case-control studies reported an inverse association between cigarette smoking during pregnancy and preeclampsia, although this association was statistically significant in only 2 of the 7 studies5, 50 (Fig 2). Case-control studies were statistically homogeneous (Q test for odds ratios, 5.9; P = .45). Overall, smok-

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Fig 3. Funnel plot of studies assessing relationship between cigarette smoking during pregnancy and preeclampsia. Cohort studies are shown as open circles and case-control studies as filled circles.

Table III. Association between cigarette smoking during pregnancy and preeclampsia according to number of cigarettes smoked per day Comparison

No. of studies

Cohort studies† <10 cigarettes/d vs nonsmokers ≥10 cigarettes/d vs nonsmokers Case-control studies5, 48, 49 <10 cigarettes/d vs nonsmokers ≥10 cigarettes/d vs nonsmokers

Typical* relative risk or odds ratio

98% Confidence interval

9 9

0.77 0.67

0.73-0.83 0.63-0.71

3 3

0.87 0.61

0.67-1.13 0.47-0.78

*Fixed effects. †References 19, 22, 26, 28, 31, 33-35, and 43.

ing in pregnancy was associated with a 32% reduction in the risk of preeclampsia (95% confidence interval, 19%43%). This risk reduction was also observed in the only study that compared a group of women with eclampsia with a healthy control group.49 Among smokers, the risk for preeclampsia decreased as the number of cigarettes smoked daily during the pregnancy increased. In fact, a meta-analysis performed on 9 cohort studies that provided data on this matter* (Table III) showed that smokers of <10 and ≥10 cigarettes/d had 23% and 33% reductions, respectively, in risk of preeclampsia. Similar findings were made with data pooled from 3 case-control studies5, 48, 49 (13% reduction risk for smokers of <10 cigarettes/d and 39% reduction risk for smokers of ≥10 cigarettes/d). The effects of smoking cessation before pregnancy *References 19, 22, 26, 28, 31, 33-35, and 43.

were evaluated in 3 studies.5, 46, 48 Women who had stopped smoking before pregnancy had a slightly but not significantly reduced risk of preeclampsia (typical odds ratio, 0.84; 95% confidence interval, 0.61-1.15). Fig 3 shows a funnel plot for the 35 studies assessing the relationship between cigarette smoking during pregnancy and the risk of preeclampsia. There was no evidence of asymmetry, and the regression approach to funnel plot asymmetry yielded an intercept of 0.15 (90% confidence interval, 0.31-0.60) and P > .10, indicating no statistical evidence of publication bias. Comment Through analysis of information gathered from cohort and case-control studies published in the worldwide literature, this systematic review confirmed that cigarette smoking during pregnancy decreases the incidence of preeclampsia. Overall, the risk of preeclampsia among

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pregnant women who smoked was 32% lower than that among nonsmoking pregnant women. This inverse association was remarkably consistent across studies conducted in different population subgroups and countries. In addition, our results showed the effect of cigarette smoking on the risk of preeclampsia to be dose-related. Despite this protective effect, however, smokers with preeclampsia had significantly higher rates of low birth weight, small for gestational age, perinatal loss, and abruptio placentae than did nonsmoking women with preeclampsia.24, 27, 38, 42 The findings obtained in our study are supported by the rigorous methods used in the identification of relevant studies (such as the lack of language restrictions, the inclusion of unpublished material, and the search of multiple electronic databases around the world), by the inclusion of all studies that met basic entry criteria with subsequent sensitivity and subgroup analyses, by the strict evaluation of methodologic quality of included studies, by the extraction and analyses of data, and by the use of funnel plot to assess the presence of biases. Several limitations of this study must be considered. First, findings of meta-analyses of observational studies may be distorted by confounding factors, the presence of bias, or both.8 Even if adjustments for confounding factors are made in original studies, residual confounding remains a potentially serious problem in observational research.60 In case-control studies, biases, in particular, selection and recall biases, are the most important threats to the validity of results. If cigarette smoking during pregnancy were unrelated to preeclampsia, however, one would expect through chance as many studies to show a direct association as an inverse association. In addition, in most studies an association between cigarette smoking and lower risk of preeclampsia was neither anticipated nor hypothesized when the study was carried out. In studies that controlled for a variety of confounding factors the findings were consistent for countries within Europe, America, and Oceania, which argues against residual confounding because it is unlikely that the same confounding factors would be operative in these diverse settings. Second, this meta-analysis, like any systematic review, is limited by the quality of existing data.61 Only 16 of 34 studies were of high quality. Exclusion of studies with lower reported methodologic quality, however, did not affect the conclusions. Also, although the overall sample was large most cases for our analyses were derived from only 3 studies.35, 38, 41 Third, there is a possibility that the relevant bibliography may not have been exhaustively identified. Databases do not include all relevant publications, nor do search strategies ensure access to all the information stored in such databases, even when searching is conducted by expert staff.62 In an attempt to minimize these problems,

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references cited in all publications found in the electronic databases were reviewed and proceedings of several international meetings on preeclampsia were consulted. Although publication bias is a potent threat to the validity of meta-analysis, it is unlikely to have had an important impact in this study. There was no evidence of funnel plot asymmetry on visual inspection, and there was no statistical evidence of asymmetry from linear regression analysis. Fourth, there was statistical evidence of heterogeneity in the cohort studies included in this meta-analysis. In an attempt to explain such heterogeneity we performed several subgroup and sensitivity analyses and found that the results from our meta-analysis were robust with respect to the choice of the statistical method, the quality of studies, the study size, the aim of the relationship between cigarette smoking and preeclampsia, and the geographic location of study. The overall estimates were virtually identical, and the confidence intervals were only slightly wider. It is unlikely that a worthwhile effect has been overlooked in this meta-analysis because the confidence intervals were quite narrow. Moreover, if a line is plotted vertically through the typical relative risk, it crosses the confidence intervals of 23 of 28 individual studies, suggesting a homogeneous set of studies. Finally, epidemiologic research on the reproductive consequences of cigarette smoking has been limited by several methodologic difficulties.63 Most studies of effects of cigarette smoking during pregnancy used questionnaire reports of exposure. Apart from the problem of reporting bias, it is plausible that women might have underreported their cigarette consumption during pregnancy because of perceptions of social or medical disapproval.64 The definition of who was a smoker and what characterized smoking consumption varied among studies. Many studies simply described women as smokers or nonsmokers or as daily smokers or nonsmokers. Therefore the proportion of occasionally smoking mothers was not expressed and detailed information on the amount and the time pattern of smoking for this group was thus not available. No study recorded some factors that may influence the actual level of exposure, such as the brand of cigarette smoked, the depth of inhalation, and individual differences in the uptake and metabolism of cigarette smoke components. Because of the variable quality of smoking data obtained from questionnaires, recent studies have used serum or urinary cotinine concentrations as an objective measure of smoke exposure in investigative associations of smoking and outcome of pregnancy.65, 66 Cotinine is the major metabolite of nicotine, and a steady-state concentration of cotinine reflects daily consumption of nicotine and accurately separates smokers from nonsmokers.67, 68 The recent study of Lain et al50 showed a reduction in the risk of preeclampsia in relation to uri-

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nary cotinine concentration. In their study (which included 50 women with preeclampsia and 50 control women without preeclampsia who were matched for gestational age, date of delivery, and body mass index) cotinine was detected in the urine of 22% and 46% of women with and without preeclampsia, respectively. Moreover, when mothers were categorized according to urinary cotinine levels as light or heavy smokers, the risk of preeclampsia was found to be lower among the women with higher cotinine levels. Our findings might be indirectly tested in randomized controlled trials that assessed the effectiveness of smoking reduction and cessation programs implemented during pregnancy. Unfortunately, no trials or systematic reviews69, 70 have reported an assessment of the impact of antismoking interventions during pregnancy on incidence of preeclampsia. Nevertheless, Suonio and Saarikoski71 have reported that pregnant Finnish women who stopped smoking during early pregnancy had an increased risk of preeclampsia (odds ratio, 1.4). The biologic mechanism by which cigarette smoking during pregnancy reduces the risk of preeclampsia is not certain. Although the etiology of preeclampsia is still unclear, several observations suggest that global endothelial dysfunction plays a central role in the pathogenesis of this disorder.72 Biochemical evidence of damaged endothelial cells has been described in women with preeclampsia: increased thromboxane A2 production,73 reduced prostacyclin biosynthesis,74 and nitric oxide deficiency.75 Several in vitro studies76-78 have consistently shown that nicotine, 1 of the >4000 different compounds found in cigarette smoke, selectively inhibits thromboxane A2 production, probably through inhibition of thromboxane synthase. Recently, it was shown that nicotine acts on nicotinic receptors in human placenta to release placental acetylcholine, which then stimulates the release of endothelium-derived relaxing factor and nitric oxide.79 Similar findings have been reported in animal in vitro studies.80 Cigarette smoking during pregnancy therefore might prevent the development of preeclampsia through nicotine-induced inhibition of thromboxane A2 synthesis, stimulation of nitric oxide release, or both. Recent research suggests that preeclampsia may be a state of immune maladaptation that may cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial cell dysfunction mediated by an increased decidual release of cytokines, especially tumor necrosis factor α and interleukins 1, 2, and 6; of proteolytic enzymes; and of free radicals.81, 82 Both in vitro83 and in vivo84, 85 studies in nonpregnant individuals have reported that nicotine inhibits the production of interleukin 2, interleukin 10, and tumor necrosis factor α by human mononuclear cells. In addition, an in vivo study86 showed that nicotine inhibits the production of oxygen free radicals, whereas another87 demonstrated

that nicotine has radical scavenging properties in vitro. Thus the beneficial effect of cigarette smoking in preeclampsia may be mediated by an inhibition of the cytokine production, by an antioxidant activity of nicotine, or both. Similar hypotheses have been mentioned to explain the decreased incidences of both ulcerative colitis83-85 and Parkinson disease87 among smokers. Implications for research. The information about the increased risk of preeclampsia among women who quit smoking during early pregnancy was obtained from an observational study. To confirm this finding beyond doubt, future randomized controlled trials on effectiveness of smoking reduction and cessation interventions during pregnancy should therefore include collection of outcome data on preeclampsia. A logical next step for future studies would be to test the possible action mechanisms of cigarette smoking on preeclampsia in animal models to identify any substance that could explain the beneficial effect reported in this study. Such substances or analogs might be then tested as therapeutic or preventive agents in preeclampsia. The consistency of the findings across studies, the presence of a dose-response relationship, the reduction in the effect with cessation of exposure, and the rise in the incidence of preeclampsia among women who stop cigarette smoking during early pregnancy all support the contention that cigarette smoking during pregnancy reduces the risk of preeclampsia. However, the well-known adverse effects of cigarette smoking during pregnancy outweigh this benefit. REFERENCES

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Appendix The following criteria were used to assess methodologic quality of the studies in this meta-analysis. Altogether 7 items were scored (providing a maximum total score of 9). A. Adjustment of risk estimates for potentially confounding factors 1. Were principal confounders in each group of subjects to be compared clearly described, and was a list of them provided? Yes, 2 points; partially, 1 point; no, 0 points. 2. Was there adequate adjustment for confounding in the analysis from which the main findings were drawn? Yes, 1 point; no or unable to determine, 0 points. B. Use of strategies to minimize bias 1. Was an attempt made to blind those measuring the main outcomes or the exposition? Yes, 1 point; no or unable to determine, 0 points. 2. Was determination of the relationship between smoking and preeclampsia stated as an aim? As primary aim, 2 points; as secondary aim, 1 point; no, 0 points. 3. Were the patients recruited from the same population? Yes, 1 point; no or unable to determine, 0 points. 4. Were losses of patients to follow-up (cohort studies) taken into account, or were the case patients and control subjects (case-control studies) recruited during the same period of time? Yes, 1 point; no or unable to determine, 0 points. C. Report of dose-response gradient. Did studies report the relationship between the number of cigarettes smoked per day during pregnancy and the risk of preeclampsia? Yes, 1 point; no, 0 points.